Noise is the most common occupational and environmental hazard, thus it is not surprising that noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, second only to age-related hearing loss (presbycusis). Although therapeutics that target the free radical pathway have shown promise for reducing NIHL, there are no FDA-approved medications for NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. Recently, we have shown that NIHL can be effectively prevented by a two-drug combination therapy targeting multiple signaling pathways. The immediate goal of this work is to extend the observed protection by this two-drug combination to two more different animal species and determine whether a synergistic effect to prevent and treat NIHL can be obtained with the same two-drug combination or drugs from the same families. The long-term goal of this program is to test, develop, and bring to market an effective drug therapy that has FDA approval for use in prevention and treatment of permanent NIHL. One category of drugs that has been highly effective in the mouse, and which will be assessed now in rats and chinchillas, includes antiepileptic drugs blocking T-type calcium channels. NIHL can also be prevented by an up-regulation of glucocorticoid signaling pathways, which led to the discovery that T-type calcium channel blockers in combination with drugs that upregulate glucocorticoids are effective against NIHL in mice. Synergistic interactions among drugs allow the dose of both drugs to be reduced, improving the safety profile of both. Based on our previous identification of a drug pair effectively against NIHL in mice from these two drug families, in this Phase I SBIR application, we will determine the median effective dose (ED50) for these two drugs to prevent and treat NIHL in rats (Aim I) and chinchillas (Aim II), and determine possible synergetic effects of these two drugs. The innovative aspects of our approach are two-fold: (1) we will focus on drugs the FDA has already approved for other disease conditions, facilitating the translation of these agents to human hearing protection trials; (2) we will use a combination therapy to intervene in multiple signaling pathways that extend beyond the free radical pathway. If protection is successful, these drugs will be evaluated for potential prevention of presbycusis and tinnitus. We will use the data from these studies, along with previously generated data, to complete an IND-enabling data package for clinical studies of these agents in human subjects.